WO2014089296A2 - Dérivés fonctionnalisés de benzamide en tant qu'agents antiviraux contre une infection à vhb - Google Patents

Dérivés fonctionnalisés de benzamide en tant qu'agents antiviraux contre une infection à vhb Download PDF

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Publication number
WO2014089296A2
WO2014089296A2 PCT/US2013/073319 US2013073319W WO2014089296A2 WO 2014089296 A2 WO2014089296 A2 WO 2014089296A2 US 2013073319 W US2013073319 W US 2013073319W WO 2014089296 A2 WO2014089296 A2 WO 2014089296A2
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Prior art keywords
optionally substituted
phenyl
carboxylic acid
amide
dioxine
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PCT/US2013/073319
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English (en)
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WO2014089296A3 (fr
Inventor
Xiaodong Xu
Timothy M. Block
Ju-Tao Guo
Yanming Du
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Institute For Hepatitis And Virus Research
Philadelphia Health & Education Corporation D/B/A Drexel University College Of Medicine
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Priority to BR112015013121A priority Critical patent/BR112015013121A2/pt
Priority to NZ708392A priority patent/NZ708392A/en
Priority to SG11201503997VA priority patent/SG11201503997VA/en
Priority to AU2013355220A priority patent/AU2013355220B2/en
Priority to KR1020157017223A priority patent/KR20150090219A/ko
Priority to EP13859675.4A priority patent/EP2928459A4/fr
Priority to JP2015545840A priority patent/JP6353460B2/ja
Priority to CA2892606A priority patent/CA2892606A1/fr
Priority to CN201380065824.0A priority patent/CN104918612B/zh
Priority to US14/650,159 priority patent/US20150307443A1/en
Application filed by Institute For Hepatitis And Virus Research, Philadelphia Health & Education Corporation D/B/A Drexel University College Of Medicine filed Critical Institute For Hepatitis And Virus Research
Publication of WO2014089296A2 publication Critical patent/WO2014089296A2/fr
Publication of WO2014089296A3 publication Critical patent/WO2014089296A3/fr
Priority to IL238930A priority patent/IL238930B/en
Priority to PH12015501276A priority patent/PH12015501276A1/en
Priority to AU2018256602A priority patent/AU2018256602A1/en
Priority to US16/202,822 priority patent/US20190092720A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/66—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/75—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/64—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D321/00—Heterocyclic compounds containing rings having two oxygen atoms as the only ring hetero atoms, not provided for by groups C07D317/00 - C07D319/00
    • C07D321/02—Seven-membered rings
    • C07D321/10—Seven-membered rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D333/70—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/72—Benzo[c]thiophenes; Hydrogenated benzo[c]thiophenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • the present invention describes novel compounds and novel methods of use of compounds as pregenomic RNA encapsidation inhibitors, useful for the treatment of Hepatitis B virus (HBV) infection and related conditions.
  • HBV Hepatitis B virus
  • HBV infection remains a major public health problem.
  • McMahon, 2005 chronically infected with HBV.
  • Approximately one-third of these individuals will die from serious liver diseases, such as cirrhosis and hepatocellular carcinoma, if left untreated (Lee, 1997; Lok, 2004).
  • Seven drugs are currently available for the management of chronic hepatitis B, which include two formulations of alpha-interferon (standard and pegylated) and five nucleos(t)ide analogues (lamivudine, adefovir, entecavir, telbivudine, and tenofovir) that inhibit HBV DNA polymerase (Keeffe et al., 2008).
  • the preferred first-line treatment choices are entecavir, tenofovir or peg-interferon alfa-2a.
  • peg- interferon alfa-2a is effective in achieving certain serological milestones in only one-third of treated patients and frequently associated with severe side effects (Janssen et al., 2005; Lau et al., 2005; Perrillo, 2009).
  • Entecavir and tenofovir are highly potent HBV inhibitors, but a long-term or possibly life-time treatment is required to continuously suppress HBV replication, which may eventually fail due to emergence of drug resistant viruses (Traditionally).
  • NIAID National Institute of Allergy and Infectious Diseases
  • HBV is a noncytopathic, liver tropic DNA virus belonging to Hepadnaviridae family.
  • Pregenomic (pg) RNA is the template for reverse transcriptional replication of HBV DNA and its encapsidation, together with viral DNA polymerase, into nucleocapsid is essential for the subsequent viral DNA synthesis. Inhibition of pregenomic RNA (pg) encapsidation would block HBV replication and provide a new therapeutic approach to the treatment of HBV.
  • inhibition of pregenomic RNA (pg) encapsidation offers the following therapeutic advantages: First, inhibition of pregenomic RNA (pg) encapsidation will complement the current medications by providing an additional option for a subpopulation of patients that do not tolerate or benefit from the current medications(Akbar et al., 2009; Liaw, 2009; Peters, 2009; Wiegand, van Bommel, and Berg). Second, based on their distinct antiviral mechanism, inhibition of pregenomic RNA (pg) encapsidation will be effective against HBV variants that are resistant to the currently available DNA polymerase inhibitors (Zoulim and Locarnini, 2009).
  • combination therapy of the inhibitors of pregenomic RNA (pg) encapsidation with DNA polymerase inhibitors should synergistically suppress HBV replication and prevent the emergence of drug resistance and thus offers a safer and more effective treatment for chronic hepatitis B infection.
  • the present invention is directed towards functionalized benzamide derivatives of the formula (I), useful as pregenomic RNA encapsidation inhibitors of HBV for the treatment of Hepatitis B virus (HBV) infection and related conditions.
  • X is selected from a group consisting of CH and S;
  • A is selected from a group consisting of hydrogen and Ci_ 4 alkyl
  • R 1 is selected from a group consisting of hydrogen, halogen, optionally substituted Ci_ 4 alkyl, optionally substituted Ci_ 4 alkenyl, C0 2 R 8 , CONHR 9 , NHCOR 10 , and OR 11 ;
  • R 1 and A are taken together with the atom to which they are bound to form an optionally substituted ring having 5-7 ring atoms;
  • R 2 is selected from a group consisting of hydrogen, halogen, optionally substituted Ci_ 4 alkyl, optionally substituted Ci_ 4 alkenyl, NHCOR 10 , and OR 11 ;
  • R 1 and R 2 are taken together with the atom to which they are bound to form an optionally substituted ring having 5-7 ring atoms optionally containing an oxygen, sulfur or nitrogen;
  • R 1 and R 2 are taken together with the atom to which they are bound to form an optionally substituted ring having 5-7 ring atoms optionally containing two atoms selected from group consisting of oxygen, sulfur and nitrogen;
  • R 3 is selected from a group consisting of hydrogen, halogen, optionally substituted Ci_ 4 alkyl, optionally substituted Ci_ 4 alkenyl;
  • R 2 and R 3 are taken together with the atom to which they are bound to form an optionally substituted ring having 5-7 ring atoms;
  • R 4 is selected from a group consisting of hydrogen, halogen, optionally substituted Ci_ alkyl, and OR 11 ;
  • R 5 is selected from a group consisting of hydrogen, halogen, optionally substituted Ci_ alkyl, and and OR 11 ;
  • R 6 is selected from a group consisting of hydrogen, halogen, optionally substituted Ci_ alkyl, and and OR 11 ;
  • R 7 is selected from a group consisting of hydrogen, halogen, optionally substituted Ci_ alkyl, and and OR 11 ;
  • R 8 is selected from a group consisting of hydrogen, optionally substituted Ci_ 4 alkyl, and optionally substituted C3-C7 cycloalkyl;
  • R 9 is selected from a group consisting of hydrogen, optionally substituted Ci_ 4 alkyl, and optionally substituted C3-C7 cycloalkyl;
  • R 10 is selected from a group consisting of hydrogen, optionally substituted Ci_ 4 alkyl, and optionally substituted C3-C7 cycloalkyl;
  • R 11 is selected from a group consisting of hydrogen, optionally substituted Ci_ 4 alkyl, and optionally substituted C3-C7 cycloalkyl; m is 0 or 1 ;
  • n 0 or 1.
  • R 12a , R 12b , R 12c , and R 12d are each independently selected from a group consisting of hydrogen, halogen, and optionally substituted Ci_ 4 alkyl.
  • R 13 is selected from a group consisting of hydrogen, halogen, optionally substituted Ci_ 4 alkyl, and optionally substituted Ci_ 4 alkenyl;
  • R 14 is selected from a group consisting of hydrogen, halogen, optionally substituted Ci_ 4 alkyl, and optionally substituted Ci_ 4 alkenyl;
  • R 14 and R 13 are taken together with the atom to which they are bound to form an optionally substituted ring having 5-7 ring atoms;
  • M is selected from a group consisting of O, S, and NH;
  • the compounds of the present invention include compounds having formula (IV):
  • R 13 is selected from a group consisting of hydrogen, halogen, optionally substituted Ci_ 4 alkyl, and optionally substituted Ci_ 4 alkenyl;
  • R 14 is selected from a group consisting of hydrogen, halogen, optionally substituted Ci_ 4 alkyl, and optionally substituted Ci_ 4 alkenyl;
  • R 14 and R 13 are taken together with the atom to which they are bound to form an optionally substituted ring having 5-7 ring atoms;
  • M is selected from a group consisting of O, S, and NH;
  • R 15a and R 15b are each independently selected from a group consisting of hydrogen, halogen, optionally substituted Ci_ 6 alkyl, and optionally substituted C 3 . 6 cycloalkyl.
  • R 15a and R 15b are taken together with the atom to which they are bound to form an optionally substituted ring having 5-7 ring atoms;
  • Y is selected from a group consisting of CH 2 , and O;
  • Z is selected from a group consisting of CH 2 , and O;
  • p is 0 or 1 ;
  • r is 0 or 1 ;
  • the compounds of the present invention include compounds having formula (VI):
  • Y is selected from a group consisting of CH 2 , and O;
  • q 0, 1 , or 2;
  • Y is selected from a group consisting of CH 2 , and O;
  • b is 0, 1 , or 2;
  • the compounds of the present invention include compounds having formula (VII):
  • R 16a , R 16b , R 16c , and R 16d are each independently selected from a group consisting of hydrogen, halogen, optionally substituted Ci_ 4 alkyl, and OR 11 .
  • the compounds of the present invention include compounds having formula (Vila):
  • R 17a , R 17b , R 17c , and R 17d are each independently selected from a group consisting of hydrogen, halogen, optionally substituted Ci_ 4 alkyl, and OR 11 .
  • compositions comprising:
  • the present invention also relates to a method for treating or preventing diseases that involve pregenomic RNA encapsidation, including, for example, HBV infection, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention.
  • the present invention yet further relates to a method for treating or preventing diseases that involve pregenomic RNA encapsidation, including, for example, HBV infection, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.
  • the present invention also relates to a method for treating or preventing disease or conditions associated with HBV infection, and diseases that involve pregenomic RNA encapsidation.
  • Said methods comprise administering to a subject an effective amount of a compound or composition according to the present invention.
  • the present invention yet further relates to a method for treating or preventing disease or conditions associated with HBV infection, and diseases that involve pregenomic RNA encapsidation, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.
  • Figure 1 Antiviral mechanism of the compounds of the present invention.
  • AML12HBV10 cells were left untreated (NT) or treated with the indicated concentrations of the compounds of the disclosure Compound 6 and Compound 19, respectively, for 2 days.
  • Bay-4109 (3 ⁇ ) or AT-61 (25 ⁇ ) served as positive controls.
  • Pregenomic RNA encapsidation inhibitors of the present invention address the clear and unmet need to identify novel and safe antiviral agents for the treatment of HBV infection that are chemically and mechanistically distinct from HBV antiviral drugs in current clinical use.
  • the pregenomic RNA encapsidation inhibitors of the present invention complement the current medications by providing an additional option for a subpopulation of patients that do not tolerate or benefit from the current medications (Akbar et al., 2009; Liaw, 2009; Peters,
  • pregenomic RNA encapsidation inhibitors of the present invention may be effective on HBV variants that are resistant to the currently available
  • RNA polymerase inhibitors Zoulim and Locarnini, 2009. Further, combination therapies of the pregenomic RNA encapsidation inhibitors of the present invention with DNA polymerase inhibitors may synergistically suppress HBV replication and prevent the emergence of drug resistance, offering a safer and more effective treatment for chronic hepatitis B (Billioud et al., 2011).
  • compositions are described as having, including, or comprising specific components, or where processes are described as having, including, or comprising specific process steps, it is contemplated that compositions of the present teachings also consist essentially of, or consist of, the recited components, and that the processes of the present teachings also consist essentially of, or consist of, the recited processing steps.
  • compositions of the present teachings also consist essentially of, or consist of, the recited components, and that the processes of the present teachings also consist essentially of, or consist of, the recited processing steps.
  • an element or component is said to be included in and/or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components and can be selected from a group consisting of two or more of the recited elements or components.
  • halogen shall mean chlorine, bromine, fluorine and iodine.
  • alkyl and/or “aliphatic” whether used alone or as part of a substituent group refers to straight and branched carbon chains having 1 to 20 carbon atoms or any number within this range, for example 1 to 6 carbon atoms or 1 to 4 carbon atoms.
  • Designated numbers of carbon atoms e.g. Ci-6 shall refer independently to the number of carbon atoms in an alkyl moiety or to the alkyl portion of a larger alkyl-containing substituent.
  • Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, wo-propyl, n-butyl, sec-butyl, wo-butyl, tert-b tyl, and the like.
  • Alkyl groups can be optionally substituted.
  • Non-limiting examples of substituted alkyl groups include hydroxymethyl, chloromethyl, trifluoromethyl, aminomethyl, 1- chloroethyl, 2-hydroxyethyl, 1 ,2-difluoroethyl, 3-carboxypropyl, and the like.
  • substituent groups with multiple alkyl groups such as (Ci- 6 alkyl) 2 amino, the alkyl groups may be the same or different.
  • alkenyl and alkynyl groups refer to straight and branched carbon chains having 2 or more carbon atoms, preferably 2 to 20, wherein an alkenyl chain has at least one double bond in the chain and an alkynyl chain has at least one triple bond in the chain.
  • Alkenyl and alkynyl groups can be optionally substituted.
  • Nonlimiting examples of alkenyl groups include ethenyl, 3-propenyl, 1-propenyl (also 2- methylethenyl), isopropenyl (also 2-methylethen-2-yl), buten-4-yl, and the like.
  • substituted alkenyl groups include 2-chloroethenyl (also 2-chloro vinyl), 4-hydroxybuten-
  • Nonlimiting examples of alkynyl groups include ethynyl, prop-2-ynyl (also propargyl), propyn-l -yl, and 2-methyl-hex-4-yn-l-yl.
  • Nonlimiting examples of substituted alkynyl groups include, 5- hydroxy-5-methylhex-3-ynyl, 6-hydroxy-6-methylhept-3-yn-2-yl, 5-hydroxy-5-ethylhept-3-ynyl, and the like.
  • cycloalkyl refers to a non-aromatic carbon-containing ring including cyclized alkyl, alkenyl, and alkynyl groups, e.g., having from 3 to 14 ring carbon atoms, preferably from 3 to 7 or 3 to 6 ring carbon atoms, or even 3 to 4 ring carbon atoms, and optionally containing one or more (e.g., 1 , 2, or 3) double or triple bond.
  • Cycloalkyl groups can be monocyclic (e.g., cyclohexyl) or polycyclic (e.g., containing fused, bridged, and/or spiro ring systems), wherein the carbon atoms are located inside or outside of the ring system. Any suitable ring position of the cycloalkyl group can be covalently linked to the defined chemical structure. Cycloalkyl rings can be optionally substituted.
  • Nonlimiting examples of cycloalkyl groups include: cyclopropyl, 2-methyl-cyclopropyl, cyclopropenyl, cyclobutyl, 2,3-dihydroxycyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctanyl, decalinyl, 2,5-dimethylcyclopentyl, 3,5-dichlorocyclohexyl, 4-hydroxycyclohexyl, 3,3,5-trimethylcyclohex-l -yl, octahydropentalenyl, octahydro-lH-indenyl, 3a,4,5,6,7,7a-hexahydro- 3H-inden-4-yl, decahydroazulenyl; bicyclo[6.2.0]de
  • cycloalkyl also includes carbocyclic rings which are bicyclic hydrocarbon rings, non-limiting examples of which include, bicyclo-[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, l ,3-dimethyl[2.2.1]heptan-2-yl, bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl.
  • Haloalkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen.
  • Haloalkyl groups include perhaloalkyl groups, wherein all hydrogens of an alkyl group have been replaced with halogens (e.g., -CF 3 , -CF 2 CF 3 ).
  • Haloalkyl groups can optionally be substituted with one or more substituents in addition to halogen.
  • haloalkyl groups include, but are not limited to, fluoromethyl, dichloroethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl groups.
  • alkoxy refers to the group -O-alkyl, wherein the alkyl group is as defined above. Alkoxy groups optionally may be substituted.
  • C 3 -C 6 cyclic alkoxy refers to a ring containing 3 to 6 carbon atoms and at least one oxygen atom (e.g., tetrahydrofuran, tetrahydro-2H- pyran). C 3 -C 6 cyclic alkoxy groups optionally may be substituted.
  • aryl wherein used alone or as part of another group, is defined herein as a an unsaturated, aromatic monocyclic ring of 6 carbon members or to an unsaturated, aromatic polycyclic ring of from 10 to 14 carbon members.
  • Aryl rings can be, for example, phenyl or naphthyl ring each optionally substituted with one or more moieties capable of replacing one or more hydrogen atoms.
  • Non-limiting examples of aryl groups include: phenyl, naphthylen-l-yl, naphthylen-2-yl, 4- fluorophenyl, 2-hydroxyphenyl, 3-methylphenyl, 2-amino-4-fluorophenyl, 2-(N,N- diethylamino)phenyl, 2-cyanophenyl, 2,6-di-tert-butylphenyl, 3-methoxyphenyl, 8- hydroxynaphthylen-2-yl 4,5-dimethoxynaphthylen-l -yl, and 6-cyano-naphthylen-l-yl.
  • Aryl groups also include, for example, phenyl or naphthyl rings fused with one or more saturated or partially saturated carbon rings (e.g., bicyclo[4.2.0]octa-l ,3,5-trienyl, indanyl), which can be substituted at one or more carbon atoms of the aromatic and/or saturated or partially saturated rings.
  • phenyl or naphthyl rings fused with one or more saturated or partially saturated carbon rings (e.g., bicyclo[4.2.0]octa-l ,3,5-trienyl, indanyl), which can be substituted at one or more carbon atoms of the aromatic and/or saturated or partially saturated rings.
  • arylalkyl refers to the group -alkyl-aryl, where the alkyl and aryl groups are as defined herein.
  • Aralkyl groups of the present invention are optionally substituted. Examples of arylalkyl groups include, for example, benzyl, 1-phenylethyl, 2-phenylethyl, 3- phenylpropyl, 2-phenylpropyl, fluorenylmethyl and the like.
  • heterocyclic and/or “heterocycle” and/or “heterocylyl,” whether used alone or as part of another group, are defined herein as one or more ring having from 3 to 20 atoms wherein at least one atom in at least one ring is a heteroatom selected from nitrogen (N), oxygen (O), or sulfur (S), and wherein further the ring that includes the heteroatom is non-aromatic.
  • the non-he teroatom bearing ring may be aryl (e.g., indolinyl, tetrahydroquinolinyl, chromanyl).
  • heterocycle groups have from 3 to 14 ring atoms of which from 1 to 5 are heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S).
  • N nitrogen
  • O oxygen
  • S sulfur
  • One or more N or S atoms in a heterocycle group can be oxidized.
  • Heterocycle groups can be optionally substituted.
  • Non-limiting examples of heterocyclic units having a single ring include: diazirinyl, aziridinyl, urazolyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolidinyl, isothiazolyl, isothiazolinyl oxathiazolidinonyl, oxazolidinonyl, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl (valerolactam), 2,3,4,5-tetrahydro-lH-azepinyl, 2,3-dihydro-lH- indole, and 1 ,2,3,4
  • heteroaryl whether used alone or as part of another group, is defined herein as one or more rings having from 5 to 20 atoms wherein at least one atom in at least one ring is a heteroatom chosen from nitrogen (N), oxygen (O), or sulfur (S), and wherein further at least one of the rings that includes a heteroatom is aromatic.
  • the non-heteroatom bearing ring may be a carbocycle (e.g., 6,7-Dihydro-5H- cyclopentapyrimidine) or aryl (e.g., benzofuranyl, benzothiophenyl, indolyl).
  • heteroaryl groups have from 5 to 14 ring atoms and contain from 1 to 5 ring heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). One or more N or S atoms in a heteroaryl group can be oxidized. Heteroaryl groups can be substituted.
  • heteroaryl rings containing a single ring include: 1,2,3,4-tetrazolyl, [l,2,3]triazolyl, [l,2,4]triazolyl, triazinyl, thiazolyl, lH-imidazolyl, oxazolyl, furanyl, thiopheneyl, pyrimidinyl, 2-phenylpyrimidinyl, pyridinyl, 3-methylpyridinyl, and 4-dimethylaminopyridinyl.
  • C 1 -C5 heteroaryl examples include, but are not limited to, triazinyl, thiazol-2-yl, thiazol-4-yl, imidazol-l-yl, lH-imidazol-2-yl, lH-imidazol-4-yl, isoxazolin-5- yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5- yl, pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl.
  • the ring when two substituents are taken together to form a ring having a specified number of ring atoms (e.g., R 2 and R 3 taken together with the nitrogen (N) to which they are attached to form a ring having from 3 to 7 ring members), the ring can have carbon atoms and optionally one or more (e.g., 1 to 3) additional heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S).
  • the ring can be saturated or partially saturated and can be optionally substituted.
  • fused ring units, as well as spirocyclic rings, bicyclic rings and the like, which comprise a single heteroatom will be considered to belong to the cyclic family corresponding to the heteroatom containing ring.
  • 1 ,2,3,4- tetrahydroquinoline having the formula:
  • aryl ring When a fused ring unit contains heteroatoms in both a saturated and an aryl ring, the aryl ring will predominate and determine the type of category to which the ring is assigned. For example, 1 ,2,3,4-tetrahydro- [l ,8]naphthyridine having the formula:
  • substituted is used throughout the specification.
  • substituted is defined herein as a moiety, whether acyclic or cyclic, which has one or more hydrogen atoms replaced by a substituent or several (e.g., 1 to 10) substituents as defined herein below.
  • the substituents are capable of replacing one or two hydrogen atoms of a single moiety at a time.
  • these substituents can replace two hydrogen atoms on two adjacent carbons to form said substituent, new moiety or unit.
  • a substituted unit that requires a single hydrogen atom replacement includes halogen, hydroxyl, and the like.
  • a two hydrogen atom replacement includes carbonyl, oximino, and the like.
  • a two hydrogen atom replacement from adjacent carbon atoms includes epoxy, and the like.
  • substituted is used throughout the present specification to indicate that a moiety can have one or more of the hydrogen atoms replaced by a substituent. When a moiety is described as “substituted” any number of the hydrogen atoms may be replaced.
  • difluoromethyl is a substituted Q alkyl
  • trifluoromethyl is a substituted Q alkyl
  • 4- hydroxyphenyl is a substituted aromatic ring
  • (N,N-dimethyl-5-amino)octanyl is a substituted C 8 alkyl
  • 3-guanidinopropyl is a substituted C 3 alkyl
  • 2-carboxypyridinyl is a substituted heteroaryl.
  • variable groups defined herein e.g., alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, aryloxy, aryl, heterocycle and heteroaryl groups defined herein, whether used alone or as part of another group, can be optionally substituted. Optionally substituted groups will be so indicated.
  • R 18 alkynyl, cycloalkyl ⁇ e.g., C 3 _6 cycloalkyl), aryl, heterocycle, or heteroaryl, or two R 18 units taken together with the atom(s) to which they are bound form an optionally substituted carbocycle or heterocycle wherein said carbocycle or heterocycle has 3 to 7 ring atoms; wherein R 19 , at each occurrence, independently is hydrogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 2 . 8 alkenyl, C 2 . 8 alkynyl, cycloalkyl ⁇ e.g., C 3 .
  • the substituents are selected from:
  • -OR 20 for example, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 ;
  • -C(0)OR 20 for example, -C0 2 CH 3 , -C0 2 CH 2 CH 3 , -C0 2 CH 2 CH 2 CH 3 ; iv) -C(0)N(R 2U ) 2 ; for example, -CONH 2 , -CONHCH 3 , -CON(CH 3 ) 2 ; v) -N(R 20 ) 2 ; for example, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NH(CH 2 CH 3 );
  • -S0 2 R 20 for example, -S0 2 H; -S0 2 CH 3 ; -S0 2 C 6 H 5 ;
  • each R 20 is independently hydrogen, optionally substituted Ci-C 6 linear or branched alkyl (e.g., optionally substituted C 1 -C 4 linear or branched alkyl), or optionally substituted C 3 -C6 cycloalkyl (e.g optionally substituted C 3 -C 4 cycloalkyl); or two R 20 units can be taken together to form a ring comprising 3-7 ring atoms.
  • each R 20 is independently hydrogen, C 1 -C6 linear or branched alkyl optionally substituted with halogen or C 3 -C6 cycloalkyl or C 3 -C6 cycloalkyl.
  • Ci_6 alkyl is specifically intended to individually disclose Ci, C 2 , C 3 , C 4 , C5, C6, C 1 -C6, C 1 -C5, C 1 -C 4 , Cr C 3 , C 1 -C 2 , C 2 -C6, C2-C5, C 2 -C4, C 2 -C 3 , C 3 -C6, C 3 -C5, C 3 -C/t, C 4 -C6, C 4 -C5, and C5-C6, alkyl.
  • composition of matter stand equally well for the pregenomic RNA encapsidation inhibitors described herein, including all enantiomeric forms, diastereomeric forms, salts, and the like, and the terms “compound,” “analog,” and “composition of matter” are used interchangeably throughout the present specification.
  • Compounds described herein can contain an asymmetric atom (also referred as a chiral center), and some of the compounds can contain one or more asymmetric atoms or centers, which can thus give rise to optical isomers (enantiomers) and diastereomers.
  • asymmetric atom also referred as a chiral center
  • the present teachings and compounds disclosed herein include such enantiomers and diastereomers, as well as the racemic and resolved, enantiomerically pure R and S stereoisomers, as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof.
  • Optical isomers can be obtained in pure form by standard procedures known to those skilled in the art, which include, but are not limited to, diastereomeric salt formation, kinetic resolution, and asymmetric synthesis.
  • the present teachings also encompass cis and trans isomers of compounds containing alkenyl moieties (e.g., alkenes and imines). It is also understood that the present teachings encompass all possible regioisomers, and mixtures thereof, which can be obtained in pure form by standard separation procedures known to those skilled in the art, and include, but are not limited to, column chromatography, thin-layer chromatography, and high-performance liquid chromatography.
  • compositions of the present teachings which can have an acidic moiety, can be formed using organic and inorganic bases. Both mono and polyanionic salts are contemplated, depending on the number of acidic hydrogens available for deprotonation.
  • Suitable salts formed with bases include metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, or magnesium salts; ammonia salts and organic amine salts, such as those formed with morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine (e.g., ethyl-tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropylamine), or a mono-, di-, or trihydroxy lower alkylamine (e.g., mono-, di- or triethanolamine).
  • metal salts such as alkali metal or alkaline earth metal salts, for example sodium, potassium, or magnesium salts
  • ammonia salts and organic amine salts such as those formed with morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-,
  • inorganic bases include NaHC0 3 , Na 2 C0 3 , KHC0 3 , K 2 C0 3 , Cs 2 C0 3 , LiOH, NaOH, KOH, NaH 2 P0 4 , Na 2 HP0 4 , and Na 3 P0 4 .
  • Internal salts also can be formed.
  • salts can be formed using organic and inorganic acids.
  • salts can be formed from the following acids: acetic, propionic, lactic, benzenesulfonic, benzoic, camphorsulfonic, citric, tartaric, succinic, dichloroacetic, ethenesulfonic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, malonic, mandelic, methanesulfonic, mucic, napthalenesulfonic, nitric, oxalic, pamoic, pantothenic, phosphoric, phthalic, propionic, succinic, sulfuric, tartaric, toluenesulfonic, and camphorsulfonic as well as other known pharmaceutically acceptable acids.
  • the terms “subject” or “patient” are used interchangeably and refer to mammals such as human patients and non-human primates, as well as experimental animals such as rabbits, rats, and mice, and other animals. Accordingly, the term “subject” or “patient” as used herein means any mammalian patient or subject to which the compounds of the invention can be administered.
  • accepted screening methods are employed to determine risk factors associated with a targeted or suspected disease or condition or to determine the status of an existing disease or condition in a subject. These screening methods include, for example, conventional work-ups to determine risk factors that may be associated with the targeted or suspected disease or condition. These and other routine methods allow the clinician to select patients in need of therapy using the methods and compounds of the present invention.
  • RNA encapsidation inhibitors of the present invention useful for the treatment of Hepatitis B virus (HBV) infection and related conditions are functionalized benzamide derivatives, and include all enantiomeric and diastereomeric forms and pharmaceutically accepted salts thereof having the formula (I):
  • X is selected from a group consisting of CH and S;
  • A is selected from a group consisting of hydrogen and Ci_ 4 alkyl
  • R 1 is selected from a group consisting of hydrogen, halogen, optionally substituted Ci_ 4 alkyl, optionally substituted C iA alkenyl, C0 2 R 8 , CONHR 9 , NHCOR 10 , and OR 11 ;
  • R 1 and A are taken together with the atom to which they are bound to form an optionally substituted ring having 5-7 ring atoms;
  • R 2 is selected from a group consisting of hydrogen, halogen, optionally substituted Ci_ 4 alkyl, optionally substituted Ci_ 4 alkenyl, NHCOR 10 , and OR 11 ;
  • R 1 and R 2 are taken together with the atom to which they are bound to form an optionally substituted ring having 5-7 ring atoms optionally containing an oxygen, sulfur or nitrogen;
  • R 1 and R 2 are taken together with the atom to which they are bound to form an optionally substituted ring having 5-7 ring atoms optionally containing two atoms selected from group consisting of oxygen, sulfur and nitrogen;
  • R 3 is selected from a group consisting of hydrogen, halogen, optionally substituted Ci_ 4 alkyl, optionally substituted Ci_ 4 alkenyl;
  • R 2 and R 3 are taken together with the atom to which they are bound to form an optionally substituted ring having 5-7 ring atoms;
  • R 4 is selected from a group consisting of hydrogen, halogen, optionally substituted Ci_ 4 alkyl, and OR 11 ;
  • R 5 is selected from a group consisting of hydrogen, halogen, optionally substituted Ci_ 4 alkyl, and and OR 11 ;
  • R 6 is selected from a group consisting of hydrogen, halogen, optionally substituted Ci_ alkyl, and and OR 11 ;
  • R 7 is selected from a group consisting of hydrogen, halogen, optionally substituted Ci_ alkyl, and and OR 11 ;
  • R 8 is selected from a group consisting of hydrogen, optionally substituted Ci_ alkyl, and optionally substituted C3-C7 cycloalkyl;
  • R 9 is selected from a group consisting of hydrogen, optionally substituted Ci_ alkyl, and optionally substituted C3-C7 cycloalkyl;
  • R 10 is selected from a group consisting of hydrogen, optionally substituted Ci_ 4 alkyl, and optionally substituted C3-C7 cycloalkyl;
  • R 11 is selected from a group consisting of hydrogen, optionally substituted Ci_ 4 alkyl, and optionally substituted C3-C7 cycloalkyl;
  • n 0 or 1 ;
  • n 0 or 1.
  • the compounds of the present invention include compounds having formula (II):
  • R 12a , R 12b , R 12c , and R 12d are each independently selected from a group consisting of hydrogen, halogen, and optionally substituted Ci_ 4 alkyl.
  • R 13 is selected from a group consisting of hydrogen, halogen, optionally substituted Ci_ 4 alkyl, and optionally substituted Ci_ 4 alkenyl;
  • R 14 is selected from a group consisting of hydrogen, halogen, optionally substituted Ci_ 4 alkyl, and optionally substituted Ci_ alkenyl;
  • R 14 and R 13 are taken together with the atom to which they are bound to form an optionally substituted ring having 5-7 ring atoms;
  • M is selected from a group consisting of O, S, and NH;
  • R 13 is selected from a group consisting of hydrogen, halogen, optionally substituted Ci_ 4 alkyl, and optionally substituted Ci_ 4 alkenyl;
  • R 14 is selected from a group consisting of hydrogen, halogen, optionally substituted Ci_ 4 alkyl, and optionally substituted Ci_ alkenyl;
  • R 14 and R 13 are taken together with the atom to which they are bound to form an optionally substituted ring having 5-7 ring atoms;
  • M is selected from a group consisting of O, S, and NH;
  • the compounds of the present invention include compounds having formula (V):
  • R 15a and R 15b are each independently selected from a group consisting of hydrogen, halogen, optionally substituted Ci_6 alkyl, and optionally substituted C 3 _6 cycloalkyl.
  • R 15a and R 15b are taken together with the atom to which they are bound to form an optionally substituted ring having 5-7 ring atoms;
  • Y is selected from a group consisting of CH 2 , and O;
  • Z is selected from a group consisting of CH 2 , and O;
  • p is 0 or 1 ;
  • r is 0 or 1 ;
  • Y is selected from a group consisting of CH 2 , and O; q is 0, 1 , or 2;
  • Y is selected from a group consisting of CH 2 , and O;
  • b is 0, 1 , or 2;
  • the compounds of the present invention include compounds having formula (VII):
  • R 16a , R 16b , R 16c , and R 16d are each independently selected from a group consisting of hydrogen, halogen, optionally substituted Ci_ 4 alkyl, and OR 11 .
  • the compounds of the present invention include compounds having formula (Vila):
  • the compounds of the present invention include compounds having formula (IX):
  • R 17a , R 17b , R 17c , and R 17d are each independently selected from a group consisting of hydrogen, halogen, optionally substituted Ci_ 4 alkyl, and OR 11 .
  • e 0, 1, or 2.
  • R 1 is hydrogen
  • R 1 is halogen
  • R 1 is optionally substituted Ci_ 4 alkyl.
  • R 1 is optionally substituted Ci_ 4 alkenyl.
  • R 1 is C0 2 R 8 - [0076] In some embodiments, R 1 is CONHR 9 .
  • R 1 is NHCOR 10 .
  • R 1 is OR 11 .
  • A is hydrogen
  • A is Ci_ 4 alkyl.
  • R 1 and A are taken together with the atom to which they are bound to form an optionally substituted ring having 5 ring atoms.
  • R 1 and A are taken together with the atom to which they are bound to form an optionally substituted ring having 6 ring atoms.
  • R 1 and A are taken together with the atom to which they are bound to form an optionally substituted ring having 7 ring atoms.
  • R 2 is hydrogen
  • R 2 is optionally substituted Ci_ 4 alkyl.
  • R 2 is NHCOR 10 .
  • R 2 is OR 11 .
  • R 1 and R 2 are taken together with the atom to which they are bound to form an optionally substituted ring having 5 ring atoms.
  • R 1 and R 2 are taken together with the atom to which they are bound to form an optionally substituted ring having 6 ring atoms.
  • R 1 and R 2 are taken together with the atom to which they are bound to form an optionally substituted ring having 7 ring atoms.
  • R 1 and R 2 are taken together with the atom to which they are bound to form an optionally substituted ring having 5 ring atoms containing an oxygen.
  • R 1 and R 2 are taken together with the atom to which they are bound to form an optionally substituted ring having 5 ring atoms containing a nitrogen.
  • R 1 and R 2 are taken together with the atom to which they are bound to form an optionally substituted ring having 6 ring atoms containing an oxygen.
  • R 1 and R 2 are taken together with the atom to which they are bound to form an optionally substituted ring having 6 ring atoms containing a sulfur.
  • R 1 and R 2 are taken together with the atom to which they are bound to form an optionally substituted ring having 7 ring atoms containing a sulfur.
  • R 1 and R 2 are taken together with the atom to which they are bound to form an optionally substituted ring having 7 ring atoms containing a nitrogen.
  • R 3 is hydrogen
  • R 3 is halogen
  • R J is optionally substituted Ci_ 4 alkenyl.
  • R 2 and R 3 are taken together with the atom to which they are bound to form an optionally substituted ring having 5 ring atoms.
  • R 2 and R 3 are taken together with the atom to which they are bound to form an optionally substituted ring having 6 ring atoms.
  • R 2 and R 3 are taken together with the atom to which they are bound to form an optionally substituted ring having 7 ring atoms.
  • R 4 is hydrogen
  • R 4 is halogen
  • R 4 is optionally substituted Ci_ 4 alkyl
  • R 4 is OR 11 .
  • R 5 is hydrogen
  • R 5 is halogen
  • R 5 is OR 11 .
  • R 6 is hydrogen
  • R 6 is halogen
  • R 6 is optionally substituted Ci_ 4 alkyl
  • R 6 is OR 11 .
  • R 7 is hydrogen
  • R 7 is halogen
  • R 7 is optionally substituted Ci_ 4 alkyl 0124] In some embodiments R 7 is OR 11 .
  • R 8 is hydrogen
  • R 8 is optionally substituted Ci_ 4 alkyl.
  • R 8 is optionally substituted C3-C7 cycloalkyl.
  • R 9 is hydrogen
  • R 9 is optionally substituted Ci_ 4 alkyl.
  • R 9 is optionally substituted C3-C7 cycloalkyl.
  • R 10 is optionally substituted Ci_ 4 alkyl.
  • R 10 is optionally substituted C3-C7 cycloalkyl.
  • R 11 is hydrogen
  • R 11 is optionally substituted Ci_ 4 alkyl
  • R 11 is optionally substituted C3-C7 cycloalkyl.
  • X is CH.
  • X is S.
  • m is 0.
  • n 1
  • n 0.
  • n is 1.
  • e is 0.
  • e is 1.
  • e is 2.
  • R 12a is hydrogen
  • R 12a is halogen
  • R 12a is optionally substituted Ci_ 4 alkyl.
  • R 12b is hydrogen
  • R 12b is halogen
  • R 12b is optionally substituted Ci_ 4 alkyl.
  • R 12c is hydrogen
  • R 12c is halogen
  • R 12c is optionally substituted Ci_ 4 alkyl. [0155] In some embodiments, R is hydrogen.
  • R I2d is halogen
  • R 12d is optionally substituted Ci_ alkyl.
  • R 13 is hydrogen
  • R 13 is halogen
  • R Ij is optionally substituted Ci_ 4 alkyl.
  • R 13 is optionally substituted Ci_ 4 alkenyl.
  • R 14 is hydrogen
  • R 14 is halogen
  • R 14 is optionally substituted Ci_ 4 alkyl.
  • R 14 is optionally substituted Ci_ 4 alkenyl.
  • R 14 and R 13 are taken together with the atom to which they are bound to form an optionally substituted ring having 5 ring atoms.
  • R 14 and R 13 are taken together with the atom to which they are bound to form an optionally substituted ring having 6 ring atoms.
  • R 14 and R 13 are taken together with the atom to which they are bound to form an optionally substituted ring having 7 ring atoms.
  • M is oxygen
  • M is sulfur
  • M is NH
  • R 15a is hydrogen
  • R 15a is halogen
  • R 15a is optionally substituted Ci_ 6 alkyl.
  • R 15a is optionally substituted C 3 . 6 cycloalkyl.
  • R 15b is hydrogen
  • R 15b is halogen
  • R 15b is optionally substituted Ci_ 6 alkyl.
  • R 15b is optionally substituted C 3 . 6 cycloalkyl.
  • R 15a and R I5b are taken together with the atom to which they are bound to form an optionally substituted ring having 5 ring atoms.
  • R I5a and R 15b are taken together with the atom to which they are bound to form an optionally substituted ring having 6 ring atoms.
  • R 15a and R 15b are taken together with the atom to which they are bound to form an optionally substituted ring having 7 ring atoms.
  • Y is CH 2 .
  • Y is oxygen
  • Z is CH 2 .
  • Z is oxygen
  • p is 0.
  • r is 0.
  • r is 1.
  • R 16a is hydrogen
  • R I6a is halogen
  • R 16a is optionally substituted Ci- 4 alkyl.
  • R 16a is OR 11 .
  • R I6b is hydrogen
  • R 16b is halogen
  • R 16b is optionally substituted CM alkyl.
  • R 16b is OR 11 .
  • R 16c is hydrogen
  • R 16c is halogen
  • R 16c is optionally substituted CM alkyl.
  • R 16c is OR 11 .
  • R 16d is hydrogen
  • R 16d is halogen
  • R 16d is OR 11 .
  • R 17a is hydrogen
  • R I7a is halogen
  • R 17 is optionally substituted CM alkyl.
  • R 17a is OR 11 .
  • R 17b is hydrogen
  • R 17b is halogen
  • R 17b is optionally substituted Ci_ 4 alkyl.
  • R 17b is OR 11 .
  • R 17c is hydrogen
  • R 17c is halogen
  • R 17c is optionally substituted Ci_ 4 alkyl.
  • R 17c is OR 11 .
  • R 17d is hydrogen
  • R 17d is halogen
  • R 17d is optionally substituted Ci_ 4 alkyl.
  • R 17d is OR 11 .
  • a compound depicted by the racemic formula will stand equally well for either of the two enantiomers having the formula or mixtures thereof, or in the case where a second chiral center is present, all diastereomers.
  • Exemplary embodiments include, but are not limited, to compounds selected from the group consisting of
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., l H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatography such as high pressure liquid chromatograpy (HPLC), gas chromatography (GC), gel-permeation chromatography (GPC), or thin layer chromatography (TLC).
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., l H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatography such as high pressure liquid chromatograpy (HPLC), gas chromatography (GC), gel-permeation chromatography (GPC), or thin layer chromatography (TLC).
  • HPLC high pressure liquid chromatograpy
  • GC gas chromatography
  • GPC gel-permeation
  • Preparation of the compounds can involve protection and deprotection of various chemical groups.
  • the need for protection and deprotection and the selection of appropriate protecting groups can be readily determined by one skilled in the art.
  • the chemistry of protecting groups can be found, for example, in Greene et al., Protective Groups in Organic Synthesis, 2d. Ed. (Wiley & Sons, 1991), the entire disclosure of which is incorporated by reference herein for all purposes.
  • Suitable solvents typically are substantially nonreactive with the reactants, intermediates, and/or products at the temperatures at which the reactions are carried out, i.e., temperatures that can range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected.
  • the compounds of these teachings can be prepared by methods known in the art of organic chemistry.
  • the reagents used in the preparation of the compounds of these teachings can be either commercially obtained or can be prepared by standard procedures described in the literature.
  • compounds of the present invention can be prepared according to the method illustrated in the General Synthetic Schemes: GENERAL SYNTHETIC SCHEMES FOR PREPARATION OF COMPOUNDS.
  • the reagents used in the preparation of the compounds of this invention can be either commercially obtained or can be prepared by standard procedures described in the literature.
  • compounds in the genus may be produced by one of the following reaction schemes.
  • the first aspect of the process of the present invention relates to a process for preparing benzamides having the formula (I).
  • Compounds of formula (I) may be prepared according to the
  • a suitably substituted compound of the formula (X) is reacted with thionyl chloride, optionally in the presence an organic solvent such as methylene chloride, dichloroethane, tetrahydronfuran, 1,4-dioxane, dimethyl formamide, and the like to provide a compound of the formula (XI).
  • a compound of the formula (X) is reacted with oxalyl chloride, optionally in the presence of dimethyl foramide, optionally in an organic solvent such as methylene chloride, dichloroethane, tetrahydronfuran, 1,4-dioxane, dimethyl formamide, and the like to provide a compound of the formula (XI).
  • a compound of the formula (XI) is then reacted with a compound of the formula (XII), a known compound or compound prepared by known methods, optionally in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, and the like, optionally in the presence of 4-N,N-dimethylaminopyridine, in an organic solvent such as methylene chloride, dichloroethane, tetrahydrofuran, 1,4-dioxane, dimethyl formamide, and the like to provide a compound of the formula (I).
  • a base such as triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, and the like
  • 4-N,N-dimethylaminopyridine in an organic solvent such as methylene chloride, dichloroethane, tetrahydrofuran, 1,4-dioxane, dimethyl formamide
  • the present invention further relates to a process for preparing compounds of the formula (IXa)).
  • a compound of the formula (XIII), a known compound or compound prepared by known methods, is reacted with a compound of the formula (XIV) in the presence of a copper salt such as Cul, CuBr, CuCl, Cu 2 S0 4 , and the like, in the presence of a base such as K 2 C0 3 , Na 2 C0 3 ,
  • H NMR spectra were recorded on a 300 MHz INOVA VARIAN spectrometer. Chemical shifts values are given in ppm and referred as the internal standard to TMS (tetramethylsilane). The peak patterns are indicated as follows: s, singlet; d, doublet; t, triplet; q, quadruplet; m, multiplet and dd, doublet of doublets. The coupling constants (J) are reported in Hertz (Hz). Mass Spectra were obtained on a 1200 Aligent LC-MS spectrometer (ES-API, Positive).
  • N-(3-phenoxyphenyl)-l-naphthamide l
  • N-(3-chlorophenyl)-l-naphthamide l
  • N-(3-chlorophenyl)-2,3-dimethoxybenzamide l
  • Example 2 Synthesis of 2,3-Dihydro-thieno[3,4-b] [l,4]dioxine-5-carboxylic acid (3-iodo- phenyl)-amide: A vial (20 mL) was charged with 2,3-dihydrothieno[3,4-b] [l,4]dioxine-5-carboxylic acid (198.0 mg, 1.06 mmol), 3-iodoaniline (233.0 mg, 1.06 mmol), O-Benzotriazole- ⁇ , ⁇ , ⁇ ', ⁇ '- tetramethyl-uronium-hexafluoro-phosphate (HBTU) (804.0 mg, 2.12 mmol), triethylamine (0.45 mL, 3.18 mmol) and DMF (2 mL).
  • HBTU O-Benzotriazole- ⁇ , ⁇ , ⁇ ', ⁇ '- tetramethyl-uronium-hexafluoro-phosphate
  • Example 3 Synthesiss of Benzo[l,3]dioxole-4-carboxylic acid (3-chloro-phenyl)- amide: Benzo[d][l,3]dioxole-4-carboxylic acid (112.5 mg, 0.68 mmol) was refluxed in thionyl chloride (4 niL) for 2 hours, and then concentrated. The residue was redissolved in dry methylene chloride (3 niL) and concentrated. This process was repeated three times.
  • the present invention also relates to compositions or formulations which comprise the pregenomic RNA encapsidation inhibitors according to the present invention.
  • the compositions of the present invention comprise an effective amount of one or more functionalized benzamide derivatives and salts thereof according to the present invention which are effective for useful for the treatment of Hepatitis B virus (HBV) infection and related conditions; and one or more excipients.
  • HBV Hepatitis B virus
  • excipients are used primarily to serve in delivering a safe, stable, and functional pharmaceutical, serving not only as part of the overall vehicle for delivery but also as a means for achieving effective absorption by the recipient of the active ingredient.
  • An excipient may fill a role as simple and direct as being an inert filler, or an excipient as used herein may be part of a pH stabilizing system or coating to insure delivery of the ingredients safely to the stomach.
  • the formulator can also take advantage of the fact the compounds of the present invention have improved cellular potency, pharmacokinetic properties, as well as improved oral bioavailability.
  • compositions that include at least one compound described herein and one or more pharmaceutically acceptable carriers, excipients, or diluents.
  • pharmaceutically acceptable carriers are well known to those skilled in the art and can be prepared in accordance with acceptable pharmaceutical procedures, such as, for example, those described in Remington's Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, PA (1985), the entire disclosure of which is incorporated by reference herein for all purposes.
  • pharmaceutically acceptable refers to a substance that is acceptable for use in pharmaceutical applications from a toxicological perspective and does not adversely interact with the active ingredient.
  • pharmaceutically acceptable carriers are those that are compatible with the other ingredients in the formulation and are biologically acceptable. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.
  • Compounds of the present teachings can be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers.
  • Applicable solid carriers can include one or more substances which can also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents, or encapsulating materials.
  • the compounds can be formulated in conventional manner, for example, in a manner similar to that used for known antiviral agents.
  • Oral formulations containing a compound disclosed herein can comprise any conventionally used oral form, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions.
  • the carrier in powders, can be a finely divided solid, which is an admixture with a finely divided compound.
  • a compound disclosed herein in tablets, can be mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets can contain up to 99 % of the compound.
  • Capsules can contain mixtures of one or more compound(s) disclosed herein with inert filler(s) and/or diluent(s) such as pharmaceutically acceptable starches (e.g., corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses (e.g., crystalline and microcrystalline celluloses), flours, gelatins, gums, and the like.
  • inert filler(s) and/or diluent(s) such as pharmaceutically acceptable starches (e.g., corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses (e.g., crystalline and microcrystalline celluloses), flours, gelatins, gums, and the like.
  • Useful tablet formulations can be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, surface modifying agents (including surfactants), suspending or stabilizing agents, including, but not limited to, magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidine, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, low melting waxes, and ion exchange resins.
  • pharmaceutically acceptable diluents including
  • Surface modifying agents include nonionic and anionic surface modifying agents.
  • Representative examples of surface modifying agents include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, magnesium aluminum silicate, and triethanolamine.
  • Oral formulations herein can utilize standard delay or time-release formulations to alter the absorption of the compound(s).
  • the oral formulation can also consist of administering a compound disclosed herein in water or fruit juice, containing appropriate solubilizers or emulsifiers as needed.
  • Liquid carriers can be used in preparing solutions, suspensions, emulsions, syrups, elixirs, and for inhaled delivery.
  • a compound of the present teachings can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, or a mixture of both, or a pharmaceutically acceptable oils or fats.
  • the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, and osmo-regulators.
  • liquid carriers for oral and parenteral administration include, but are not limited to, water (particularly containing additives as described herein, e.g., cellulose derivatives such as a sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and arachis oil).
  • the carrier can be an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
  • the liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellants.
  • Liquid pharmaceutical compositions which are sterile solutions or suspensions, can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously.
  • Compositions for oral administration can be in either liquid or solid form.
  • the pharmaceutical composition is in unit dosage form, for example, as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories.
  • the pharmaceutical composition can be sub-divided in unit dose(s) containing appropriate quantities of the compound.
  • the unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids.
  • the unit dosage form can be a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
  • Such unit dosage form can contain from about 1 mg/kg of compound to about 500 mg/kg of compound, and can be given in a single dose or in two or more doses.
  • Such doses can be administered in any manner useful in directing the compound(s) to the recipient's bloodstream, including orally, via implants, parenterally (including intravenous, intraperitoneal and subcutaneous injections), rectally, vaginally, and transdermally.
  • an effective dosage can vary depending upon the particular compound utilized, the mode of administration, and severity of the condition being treated, as well as the various physical factors related to the individual being treated.
  • a compound of the present teachings can be provided to a patient already suffering from a disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications.
  • the dosage to be used in the treatment of a specific individual typically must be subjectively determined by the attending physician.
  • the variables involved include the specific condition and its state as well as the size, age and response pattern of the patient.
  • the compounds of the present teachings can be formulated into a liquid composition, a solid composition, or an aerosol composition.
  • the liquid composition can include, by way of illustration, one or more compounds of the present teachings dissolved, partially dissolved, or suspended in one or more pharmaceutically acceptable solvents and can be administered by, for example, a pump or a squeeze- actuated nebulized spray dispenser.
  • the solvents can be, for example, isotonic saline or bacteriostatic water.
  • the solid composition can be, by way of illustration, a powder preparation including one or more compounds of the present teachings intermixed with lactose or other inert powders that are acceptable for intrabronchial use, and can be administered by, for example, an aerosol dispenser or a device that breaks or punctures a capsule encasing the solid composition and delivers the solid composition for inhalation.
  • the aerosol composition can include, by way of illustration, one or more compounds of the present teachings, propellants, surfactants, and co-solvents, and can be administered by, for example, a metered device.
  • the propellants can be a chlorofluorocarbon (CFC), a hydrofluoroalkane (HFA), or other propellants that are physiologically and environmentally acceptable.
  • Compounds described herein can be administered parenterally or intraperitoneally.
  • Solutions or suspensions of these compounds or a pharmaceutically acceptable salts, hydrates, or esters thereof can be prepared in water suitably mixed with a surfactant such as hydroxyl- propylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations typically contain a preservative to inhibit the growth of microorganisms.
  • the pharmaceutical forms suitable for injection can include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In some embodiments, the form can sterile and its viscosity permits it to flow through a syringe.
  • the form preferably is stable under the conditions of manufacture and storage and can be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • Compounds described herein can be administered transdermally, i.e., administered across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues. Such administration can be carried out using the compounds of the present teachings including pharmaceutically acceptable salts, hydrates, or esters thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).
  • Transdermal administration can be accomplished through the use of a transdermal patch containing a compound, such as a compound disclosed herein, and a carrier that can be inert to the compound, can be non-toxic to the skin, and can allow delivery of the compound for systemic absorption into the blood stream via the skin.
  • the carrier can take any number of forms such as creams and ointments, pastes, gels, and occlusive devices.
  • the creams and ointments can be viscous liquid or semisolid emulsions of either the oil-in- water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the compound can also be suitable.
  • occlusive devices can be used to release the compound into the blood stream, such as a semi-permeable membrane covering a reservoir containing the compound with or without a carrier, or a matrix containing the compound.
  • Other occlusive devices are known in the literature.
  • Compounds described herein can be administered rectally or vaginally in the form of a conventional suppository.
  • Suppository formulations can be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository' s melting point, and glycerin.
  • Water-soluble suppository bases such as polyethylene glycols of various molecular weights, can also be used.
  • Lipid formulations or nanocapsules can be used to introduce compounds of the present teachings into host cells either in vitro or in vivo. Lipid formulations and nanocapsules can be prepared by methods known in the art. [0302] To increase the effectiveness of compounds of the present teachings, it can be desirable to combine a compound with other agents effective in the treatment of the target disease. For example, other active compounds (i.e., other active ingredients or agents) effective in treating the target disease can be administered with compounds of the present teachings. The other agents can be administered at the same time or at different times than the compounds disclosed herein.
  • Compounds of the present teachings can be useful for the treatment or inhibition of a pathological condition or disorder in a mammal, for example, a human subject.
  • the present teachings accordingly provide methods of treating or inhibiting a pathological condition or disorder by providing to a mammal a compound of the present teachings including its pharmaceutically acceptable salt) or a pharmaceutical composition that includes one or more compounds of the present teachings in combination or association with pharmaceutically acceptable carriers.
  • Compounds of the present teachings can be administered alone or in combination with other therapeutically effective compounds or therapies for the treatment or inhibition of the pathological condition or disorder.
  • compositions according to the present invention include from about 0.001 mg to about 1000 mg of one or more pregenomic RNA encapsidation inhibitors according to the present invention and one or more excipients; from about 0.01 mg to about 100 mg of one or more pregenomic RNA encapsidation inhibitors according to the present invention and one or more excipients; and from about 0.1 mg to about 10 mg of one or more pregenomic RNA encapsidation inhibitors according to the present invention; and one or more excipients.
  • the HBV replication inhibitors of the present invention are capable of treating and preventing diseases associated with HBV infection.
  • the results presented in Table 1 demonstrated that compounds of the present invention inhibit HBV replication in an immortalized murine hepatocyte (AML12)-derived stable cell line (AML12HBV10) that supports robust HBV replication in a tetracycline inducible manner without measurable cytotoxicity up to 50 ⁇ by using the standard MTT assay (Promega).
  • AML12HBV10 is an immortalized murine hepatocyte
  • AML12 (AML12)-derived stable cell line that supports robust HBV replication in a tetracycline inducible manner (Xu et al.)-
  • the cells were seeded into 96 well plates at a density of 2 x 10 4 cells per well and cultured in DMEM/F12 media with 10% fetal bovine serum in the absence of tetracycline to allow pgRNA transcription and HBV DNA replication.
  • DMEM/F12 media 10% fetal bovine serum in the absence of tetracycline to allow pgRNA transcription and HBV DNA replication.
  • Cells were then lysed by adding into each well of 100 ⁇ lysis buffer containing 10 mM Tris-HCl (pH 7.6), 1 mM EDTA, 100 mM NaCl and 1% NP-40 and incubated at 37 °C for 30 minutes. Half amount (50 ⁇ ) of cell lysate from each well was combined with equal volume of denaturing solution containing 0.5N NaOH and 1.5M NaCl. After 5 minute incubation, 100 ⁇ of neutralization solution (1M Tris-HCl, pH 7.4, 1.5M NaCl) was added into each well. The denatured cell lysates (totally 200 ⁇ ) were applied onto Nylon membrane using 96-well dot-blot manifold (Biorad).
  • HBV DNA in the cell lysates were determined by dot-blot hybridization with alpha- 32 P-UTP-labelled riboprobe specific for HBV minus strand DNA.
  • the antiviral efficacy of a compound of the disclosure was expressed as the concentration that reduces the amount of HBV DNA by 50% (EC 50 ).
  • AML12HBV10 cells were seeded into 96-well plates at a density of 2 x 10 4 cells per well and cultured in DMEM/F12 media with 10% fetal bovine serum in the absence of tetracycline to allow pgRNA transcription and HBV DNA replication.
  • DMEM/F12 media 10% fetal bovine serum in the absence of tetracycline to allow pgRNA transcription and HBV DNA replication.
  • One day after seeding cells were left untreated or treated with a serial dilution of testing compounds, ranging from 50 ⁇ to 0.39 ⁇ , for 48 hours.
  • the cell viability was measured by a MTT assay, following procedure provided by the manufacturer (Promega).
  • the cytotoxicity of a compound was expressed as the concentration of compound that reduces the viability of the cells by 50% (CC 50 ).
  • the cells were mock-treated or treated with a serial dilution of compounds of the disclosure, ranging from 10 ⁇ to 0.018 ⁇ , for 6 days in the absence of tetracycline.
  • a serial dilution of compounds of the disclosure ranging from 10 ⁇ to 0.018 ⁇ , for 6 days in the absence of tetracycline.
  • cells were lysed by adding into each well of the 12-well plates 0.5 ml of lysis buffer containing 10 mM Tris-HCl (pH 8.0), 1 mM EDTA, 1% NP40 and 2% sucrose and incubating at 37°C for 10 minutes. Cell debris and nuclei were removed by centrifugation and the supernatant was mixed with 130 ⁇ of 35% polyethylene glycol (PEG) 8000 containing 1.5 M NaCl.
  • PEG polyethylene glycol
  • viral nucleocapsids were pelleted by centrifugation at 6,000 X g for 5 min at 4°C, followed by 1 hour digestion at 37°C in 400 ⁇ of digestion buffer containing 0.5 mg/ml pronase (Calbiochem), 0.5% SDS, 150 mM NaCl, 25 mM Tris-HCl (pH 8.0) and 10 mM EDTA.
  • the digestion mixture was extracted twice with phenol and DNA was precipitated with ethanol, dissolved in TE buffer (10 mM Tris-HCl, pH 8.0; 0.1 mM EDTA). One half of the DNA sample from each well was resolved by electrophoresis into a 1.5% agarose gel.
  • the gel was then subjected to denaturation in a solution containing 0.5 M NaOH and 1.5 M NaCl, followed by neutralization in a buffer containing 1 M Tris- HCl (pH7.4) and 1.5 M NaCl. DNA was then blotted onto Hybond-XL membrane (GE Health care) in 20X SSC buffer. The amounts of cytoplasmic HBV core-associated HBV DNA were determined by Southern blot hybridization and the antiviral efficacy of a compound was expressed as its concentration that reduce the amount of HBV DNA by 50% (EC 50 ) or 90% (EC 90 ).
  • HBV mRNA was extracted with TRIzol reagents (Invitrogen). Five micrograms of total RNA was resolved in 1.5% agarose gel containing 2.2 M formadelhyde and transferred onto Hybond-XL membrane in 20X SSC buffer. The amounts of HBV mRNA were determined by Northern blot hybridization with an alpha- 32 P-UTP labeled riboprobe specific for plus strand of HBV genome.
  • AML12HBV10 cells were lysed by addition of 600 ⁇ of lysis buffer (50 mM Tris-HCl [pH 7.5], 1 mM EDTA, 150 mM NaCl, 1% NP-40) into each well of 12-well plates. The nuclei were removed by centrifugation at 5,000g for 10 minutes. One-half of the sample was mixed with 6 U of micrococcal nuclease (Pharmacia) and 15 ⁇ of 100 mM CaCl 2 and incubated for 15 minutes at 37 °C to digest free nucleic acids.
  • lysis buffer 50 mM Tris-HCl [pH 7.5], 1 mM EDTA, 150 mM NaCl, 1% NP-40
  • the reaction was stopped with 6 ⁇ of 0.5 M EDTA, and capsids were precipitated by adding 125 ⁇ of 35% polyethylene glycol 8000 in 1.75 M NaCl to the reaction and incubating in ice for 30 minutes, followed by centrifugation at 6,000g for 10 minutes at 4 °C. Pellets were re-suspended in 50 ⁇ of TNE buffer (10 mM Tris-HCl [pH 8], 100 mM NaCl, 1 mM EDTA). pgRNA was extracted by the addition of 1 ml of Trizol reagent.
  • the encapsidated pgRNA were electrophoresed through a 2.2 M formaldehyde- 1% agarose gel, transferred to a nylon membrane, and immobilized by UV cross- linking (Stratagene). Hybridization was performed with an alpha- 32 P-UTP labeled riboprobe specific for plus strand of HBV genome.
  • AML12HB10 cells were lysed by addition of 300 ⁇ buffer containing lOmM Tris-HCl (pH7.6), 100 mM NaCl, 1 mM EDTA and 0.1% NP-40 to each well of 12-well plate. Cell debries were removed by centrifugation at 5000 g for 10 minutes.
  • HBV capsids were detected by probing the membrane with an antibody against HBV core protein (DAKO). Bound antibody was revealed by IRDye secondary antibobies and visualized by Li-COR Odyssey system.
  • DAKO HBV core protein
  • the membrane were treated with buffer containing 0.5N NaOH and 1.5 M NaCl for 5 minutes and followed by neutralization with buffer containing 1 M TRIS-HCl and 1.5M NaCl for 5 minutes.
  • the viral DNA was detected by hybridization with a a- 32 P- UTP (800Ci/mmol, Perkin Elmer) labeled minus strand specific full-length HBV riboprobe (Xu et al.).
  • the gel was then subjected to denaturation in a solution containing 0.5 M NaOH and 1.5 M NaCl, followed by neutralization in a buffer containing 1 M Tris-HCl (pH7.4) and 1.5 M NaCl. DNA was then blotted onto Hybond-XL membrane (GE Health care) in 20X SSC buffer.
  • the HBV DNA replication intermediates were probed with an alpha- 32 P-UTP labeled riboprobe specific for minus strand of HBV genome.

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Abstract

L'invention concerne des compositions pharmaceutiques comprenant des dérivés fonctionnalisés de benzamide utiles en tant qu'inhibiteurs d'encapsidation d'ARN prégénomique, utiles pour le traitement d'une infection par le virus de l'hépatite B (VHB).
PCT/US2013/073319 2012-12-06 2013-12-05 Dérivés fonctionnalisés de benzamide en tant qu'agents antiviraux contre une infection à vhb WO2014089296A2 (fr)

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CN201380065824.0A CN104918612B (zh) 2012-12-06 2013-12-05 作为抗hbv感染的抗病毒剂的官能化苯甲酰胺衍生物
SG11201503997VA SG11201503997VA (en) 2012-12-06 2013-12-05 Functionalized benzamide derivatives as antiviral agents against hbv infection
AU2013355220A AU2013355220B2 (en) 2012-12-06 2013-12-05 Functionalized benzamide derivatives as antiviral agents against HBV infection
KR1020157017223A KR20150090219A (ko) 2012-12-06 2013-12-05 Hbv 감염에 대항하여 항바이러스 물질로써 기능화된 벤자미드 유도체들
EP13859675.4A EP2928459A4 (fr) 2012-12-06 2013-12-05 Dérivés fonctionnalisés de benzamide en tant qu'agents antiviraux contre une infection à vhb
JP2015545840A JP6353460B2 (ja) 2012-12-06 2013-12-05 Ｈｂｖ感染に対する抗ウイルス剤としての官能化ベンズアミド誘導体
CA2892606A CA2892606A1 (fr) 2012-12-06 2013-12-05 Derives fonctionnalises de benzamide en tant qu'agents antiviraux contre une infection a vhb
BR112015013121A BR112015013121A2 (pt) 2012-12-06 2013-12-05 derivados funcionalizados de benzamida como agentes antivirais contra infecção por hbv
NZ708392A NZ708392A (en) 2012-12-06 2013-12-05 Functionalized benzamide derivatives as antiviral agents against hbv infection
US14/650,159 US20150307443A1 (en) 2012-12-06 2013-12-05 Functionalized benzamide derivatives as antiviral agents against hbv infection
IL238930A IL238930B (en) 2012-12-06 2015-05-20 History Benzamide functions as an antiviral agent against HBV infections
PH12015501276A PH12015501276A1 (en) 2012-12-06 2015-06-05 Functionalized benzamide derivatives as antiviral agents against hbv infection
AU2018256602A AU2018256602A1 (en) 2012-12-06 2018-11-01 Functionalized benzamide derivatives as antiviral agents against hbv infection
US16/202,822 US20190092720A1 (en) 2012-12-06 2018-11-28 Functionalized benzamide derivatives as antiviral agents against hbv infection

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WO2017048954A1 (fr) 2015-09-15 2017-03-23 Assembly Biosciences, Inc. Modulateurs des protéines du noyau de l'hépatite b
WO2018053157A1 (fr) 2016-09-15 2018-03-22 Assembly Biosciences, Inc. Modulateurs des protéines du noyau de l'hépatite b
WO2018085619A1 (fr) 2016-11-07 2018-05-11 Arbutus Biopharma, Inc. Composés tricycliques contenant de la pyridinone substituée, et procédés les utilisant
JP2018514575A (ja) * 2015-05-04 2018-06-07 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ Ｂ型肝炎ウイルス感染症の治療用のＨＢｓＡｇ（ＨＢＶ表面抗原）及びＨＢＶ ＤＮＡ産生の阻害剤としてのテトラヒドロピリドピリミジン類及びテトラヒドロピリドピリジン類
WO2018160878A1 (fr) 2017-03-02 2018-09-07 Assembly Biosciences, Inc. Composés de sulfamide cyclique et leurs procédés d'utilisation
WO2018172852A1 (fr) 2017-03-21 2018-09-27 Arbutus Biopharma Corporation Dihydroindène-4-carboxamides substitués, leurs analogues et procédés d'utilisation correspondant
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EP2928459A2 (fr) 2015-10-14
SG10201900695PA (en) 2019-02-27
IL238930B (en) 2020-06-30
WO2014089296A3 (fr) 2014-08-07
CN104918612B (zh) 2019-10-25
JP2016506387A (ja) 2016-03-03
US20190092720A1 (en) 2019-03-28
EP2928459A4 (fr) 2016-10-26
CN110642741A (zh) 2020-01-03
IL238930A0 (en) 2015-07-30
JP2018162272A (ja) 2018-10-18
AU2013355220A1 (en) 2015-06-18
JP6353460B2 (ja) 2018-07-04
BR112015013121A2 (pt) 2017-07-11
NZ708392A (en) 2020-05-29
NZ748966A (en) 2020-05-29
CA2892606A1 (fr) 2014-06-12
US20150307443A1 (en) 2015-10-29
AU2013355220B2 (en) 2018-08-02
AU2018256602A1 (en) 2018-11-22
SG11201503997VA (en) 2015-06-29
KR20150090219A (ko) 2015-08-05
CN104918612A (zh) 2015-09-16
PH12015501276A1 (en) 2015-08-24

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